In one sense, pharmacology can be considered a “good
news, bad news” scenario. The good news is that
exciting and innovative changes in drug therapy continue
to occur at lightning speed. The bad news is that
it is often difficult for health care practitioners to stay
abreast of this rapidly changing field. Oftentimes,
drug therapies that were considered state-of-the-art
only a few years ago are now outdated and replaced by
more contemporary treatments.

The reality is more complex since the receptor binding profile of clozapine and the newer atypical antipsychotic agents suggests that D2-receptor blockade is not essential for antipsychotic effect. The atypical drugs act on numerous receptors and modulate several interacting transmitter systems. Clozapine is a highly effective antipsychotic. It has little affinity for the D2-receptor compared with classical drugs but binds more avidly to other dopamine subtypes (e.g. D1, D3 and D4). It blocks muscarinic acetylcholine receptors, as do certain classical agents (e.g.

Increasing evidence suggests that serious mental illness is neurodevelopmental and the
onset of pre-psychotic symptoms occurs in adolescence, at a time when the cerebral cortex is
still developing. As with many complex disorders (e.g. hypertension, epilepsy, and
diabetes), there appear to be many aetiological pathways that might lead to the final mixture
of behavioral signs and symptoms we label ‘schizophrenia’.

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We have shown that quetiapine, a new antipsychotic drug, protects cultured
cells against oxidative stress-related cytotoxicities induced by amyloidb
(Ab)25-35, and that quetiapine prevents memory impairment and decreases
Abplaques in the brains of amyloid precursor protein (APP)⁄presenilin-1
(PS-1) double-mutant mice.

This chapter will concentrate on the mechanisms by which drugs alter neurotransmission
of relevance to the treatment of psychiatric disorders.
■ The major site of action for drugs used in psychiatry is the synapse and in particular
those utilising amines or amino acids as neurotransmitters.
■ The majority of the drugs act either presynaptically to influence levels of the
neurotransmitter in the synaptic cleft, or by altering the functional state of the
postsynaptic receptors.

The lack of understanding of the mechanisms whereby the above aetiological
factors (genetic and environmental) interact to initiate the complex pathobiology of
schizophrenia is the key reason for the relative lack of progress in the development of novel
drug treatments. All the antipsychotic medication that is currently in use (first and second
generation) is all predicated on the so-called ‘Dopamine Hypothesis’ (discussed below) and
share a common putative mechanism of action, namely dopamine antagonism.

The results of the BMJ Clinical Evidence review tend to indicate that as far as
antipsychotic medication goes, current drugs are of some, if limited, efficacy in many
patients, and that most drugs cause side effects in most patients. Although this is a rather
downbeat conclusion, this will not be too surprising to clinicians in the field, given their
clinical experience and our knowledge of the pharmacology of the available antipsychotic
medication.

During our first visit, Sara seemed distracted. She was a pleasant, middleaged
woman who had never sought care from a psychiatrist. Several months earlier
she had begun to feel tired and irritable; she thought she had the flu. When her 25-
year-old son called to say that he was getting a divorce, she began to cry. “I worried I
had done something to break up his marriage,” she told me, dabbing at her eyes. “I
felt so guilty.” Over the following months she became depressed and so preoccupied
that she often forgot to pay bills.